Cardiotoxicity is mitigated after a supervised exercise program in HER2-positive breast cancer undergoing adjuvant trastuzumab

Abstract

BackgroundTrastuzumab is used, alone or in conjunction with standard chemotherapy, to treat HER2-positive breast cancer (BC). Although it improves cancer outcomes, trastuzumab. can lead to cardiotoxicity. Physical exercise is a safe and effective supportive therapy in the management of side effects, but the cardioprotective effects of exercise are still unclear.ObjectivesThe primary aim of this study was to test whether trastuzumab-induced cardiotoxicity [left ventricular ejection fraction (LVEF) under 50%, or an absolute drop in LVEF of 10%] was reduced after a supervised exercise program of 3 months in patients with HER2-positive breast cancer. Secondary endpoints were to evaluate (i) cardiotoxicity rates using other criteria, (ii) cardiac parameters, (iii) cardiorespiratory fitness and (iv) whether a change in LVEF influences the cardiorespiratory fitness.Methods89 women were randomized to receive adjuvant trastuzumab in combination with a training program (training group: TG; n = 46) or trastuzumab alone (control group: CG; n = 43). The primary and secondary endpoints were evaluated at the end of the supervised exercise program of 3 months (T3).ResultsAfter exercise program, 90.5 % of TG patients and 81.8% of CG patients did not exhibit cardiotoxicity. Furthermore, whatever the used criterion, percentage of patients without cardiotoxicity were greater in TG (97.6 and 100% respectively) than in CG (90.9 and 93.9% respectively). LVEF and GLS values remained stable in both groups without any difference between the groups. In contrast, at T3, peak VO2 (+2.6 mL.min−1.kg−1; 95%CI, 1.8 to 3.4) and maximal power (+21.3 W; 95%CI, 17.3 to 25.3) increased significantly in TG, whereas they were unchanged in CG (peak VO2: +0.2 mL.min−1.kg−1; 95%CI, −0.5 to 0.9 and maximal power: +0.7 W, 95%CI, −3.6 to 5.1) compared to values measured at T0. No correlation between LVEF changes and peak VO2 or maximal power was observed.ConclusionA 12-week supervised exercise regimen was safe and improved the cardiopulmonary fitness in particular peak VO2, in HER2-positive BC patients treated with adjuvant trastuzumab therapy. The study is under powered to come to any conclusion regarding the effect on cardiotoxicity.Clinical trial registrationwww.ClinicalTrials.gov, identifier: NCT02433067.

Exercise for the Prevention of Anthracycline-Induced Functional Disability and Cardiac Dysfunction: The BREXIT Study

“…Although there is strong preclinical evidence for cardioprotection, 11 previous randomized trials of ExT during AC or human epidermal growth factor receptor 2–targeted therapy have failed to show a beneficial effect of ExT on cardiac function. 33,37–39 The improvements in cardiac function observed in our study may have been attributable to the higher dose and varied nature of the exercise stimulus (including high-intensity interval training). On the other hand, the lack of evidence for ExT-associated cardioprotection may be attributable to a historical reliance on resting measures of cardiac function (ie, LVEF and GLS).…”

A Review on the Role of Exercise Training to Prevent a Decline in Cardiorespiratory Fitness and Cardiac Function in Breast Cancer Survivors

“…19,20,[36][37][38][39] Two studies have assessed the impact of 3-4 mo of aerobic ExT during HER2-targeted therapy. 40,41 In a single-arm study of BCS undergoing HER2-targeted therapy, Haykowsky et al 41 reported no impact of 4 mo of 3 sessions/wk of MCT on V ˙O2peak (+1.9 mL/kg/min, P = .2). In contrast, Jacquinot et al 40 reported that 12 wk of 3 sessions/wk of HIIT was associated with a 2.6 mL/kg/min improvement in V ˙O2peak .…”

“…40,41 In a single-arm study of BCS undergoing HER2-targeted therapy, Haykowsky et al 41 reported no impact of 4 mo of 3 sessions/wk of MCT on V ˙O2peak (+1.9 mL/kg/min, P = .2). In contrast, Jacquinot et al 40 reported that 12 wk of 3 sessions/wk of HIIT was associated with a 2.6 mL/kg/min improvement in V ˙O2peak . The lack of V ˙O2peak improvement seen with the study of Haykowsky et al 41 may relate to the smaller sample size (n = 17 41 vs n = 75 40 ) and relatively modest adherence (60% of sessions attended 41 ).…”

“…35 Fewer studies have assessed the impact on resting GLS, but available evidence shows no effect of ExT on GLS-which typically shows a small reduction of negligible clinical significance. 19,20,40,46,47 In addition, no studies have demonstrated that ExT prevents clinical cardiac dysfunction during AC and/or HER2-targeted therapy (based on guideline-based LVEF ± GLS criteria). 19,20,40,46 This may reflect the small sample sizes, small changes in resting cardiac function, and/ or low rates of cardiac dysfunction reported in the majority of studies.…”

“…19,20,40,46,47 In addition, no studies have demonstrated that ExT prevents clinical cardiac dysfunction during AC and/or HER2-targeted therapy (based on guideline-based LVEF ± GLS criteria). 19,20,40,46 This may reflect the small sample sizes, small changes in resting cardiac function, and/ or low rates of cardiac dysfunction reported in the majority of studies. The discordance between ExT-induced changes in V ˙O2peak and resting left-ventricular (LV) function (which is the core component of cardiotoxicity definitions) also highlights the insensitivity of resting measures to detect clinically meaningful changes in CRF and cardiac function (Figure 2).…”